https://doi.org/10.1590/0004-282X20200051 VIEW AND REVIEW
ABSTRACT
Background: As the COVID-19 pandemic unfolds worldwide, different forms of reports have described its neurologic manifestations. Objective: To review the literature on neurological complications of SARS-CoV-2 infection. Methods: Literature search performed following systematic reviews guidelines, using specific keywords based on the COVID-19 neurological complications described up to May 10th, 2020.
Results: A total of 43 articles were selected, including data ranging from common, non-specific symptoms, such as hyposmia and myalgia, to more complex and life-threatening conditions, such as cerebrovascular diseases, encephalopathies, and Guillain-Barré syndrome. Conclusion: Recognition of neurological manifestations of SARS-CoV-2 should be emphasized despite the obvious challenges faced by clinicians caring for critical patients who are often sedated and presenting other concurrent systemic complications.
Keywords: Coronavirus Infections; COVID-19; Neurology; Guillain-Barré Syndrome; Encephalitis; Stroke. RESUMO
Introdução: À medida que a pandemia da COVID-19 se desenvolve em todo o mundo, diferentes tipos de publicações descreveram suas manifestações neurológicas. Objetivo: Revisar a literatura sobre complicações neurológicas da infecção por SARS-CoV-2. Métodos: A pesquisa bibliográfica foi realizada seguindo diretrizes de revisões sistemáticas, usando palavras-chave específicas baseadas nas complicações neurológicas da COVID-19 descritas até 10 de maio de 2020. Resultados: Foram selecionados 43 artigos, incluindo descrições que variam de sintomas comuns e inespecíficos, como hiposmia e mialgia, a condições mais complexas e com risco de vida, como doenças cerebrovasculares, encefalopatias e síndrome de Guillain-Barré. Conclusão: O reconhecimento das manifestações neurológicas da SARS-CoV-2 deve ser enfatizado apesar dos óbvios desafios enfrentados pelos clínicos que cuidam de pacientes críticos, muitas vezes sedados e apresentando outras complicações sistêmicas concomitantes.
Palavras-chave: Infecções por Coronavírus; COVID-19; Neurologia; Síndrome de Guillain-Barré; Encefalopatias; Acidente Vascular Cerebral; Mialgia.
Neurological complications in patients with
SARS-CoV-2 infection: a systematic review
Complicações neurológicas em pacientes infectados pelo SARS-CoV-2: uma revisão sistemática
Renato Puppi MUNHOZ1, José Luiz PEDROSO2, Fábio Augusto NASCIMENTO3, Sergio Monteiro de ALMEIDA4,
Orlando Graziani Povoas BARSOTTINI2, Francisco Eduardo C CARDOSO5, Hélio A Ghizoni TEIVE6
1University of Toronto, Toronto Western Hospital, Movement Disorders Centre, Toronto ON, Canada.
2Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of Neurology and Neurosurgery, São Paulo SP, Brazil. 3Baylor College of Medicine, Department of Neurology, Houston TX, USA.
4Universidade Federal do Paraná, Hospital de Clínicas, Neuroinfection Outclinic, Virology Laboratory, Medical Pathology Department, Curitiba PR, Brazil. 5Universidade Federal de Minas Gerais, Hospital das Clínicas, Movement Disorders Unit, Neurology Service, Internal Medicine Department, Belo
Horizonte MG, Brazil.
6Universidade Federal do Paraná, Hospital de Clínicas, Internal Medicine Department, Neurology Service, Curitiba PR, Brazil.
Renato Puppi MUNHOZ https://orcid.org/0000-0002-4783-4067; José Luiz PEDROSO https://orcid.org/0000-0002-1672-8894;
Fábio Augusto NASCIMENTO https://orcid.org/0000-0002-7161-6385; Sergio Monteiro de ALMEIDA https://orcid.org/0000-0001-5690-105X;
Orlando Graziani Povoas BARSOTTINI https://orcid.org/0000-0002-0107-0831; Francisco Eduardo C CARDOSO https://orcid.org/0000-0003-0808-0116; Hélio A Ghizoni TEIVE https://orcid.org/0000-0003-2305-1073
Correspondence: Renato Puppi Munhoz; E-mail: renato.munhoz@uhn.ca Conflict of interest: There is no conflict of interest to declare.
Received on April 15, 2020; Received in its final form on April 27, 2020; Accepted on May 1, 2020.
INTRODUCTION
Coronaviruses (CoV) belong to the Coronaviridae family,
Nidovirales order. These viruses are enveloped, have a
positive-sense single-stranded RNA genome and are classified into four
genera: alpha, beta, gamma, and delta. The alpha, beta, and
delta CoV infect mammals. However, they all have the ability
to jump between species, leading to the emergence of severe respiratory syndromes in humans, such as the Middle East respiratory syndrome (MERS) caused by MERS-CoV, the severe acute respiratory syndrome (SARS) caused by SARS-CoV, and,
more recently, COVID-19, caused by SARS-CoV-2.1
CoV-related disease was first described in 1931, with the isolation of the first human virus per se (HCoV-229E) in 1965.
Until the epidemic of SARS in late 2002, only two human CoV types were known — HCoV-229E and HCoV-OC43. Since then, another six human CoV have been identified, impli-cated as causes of cold (2 to 10%), the second most com-mon after rhinoviruses, manifesting in adults with limited symptoms, including rhinitis, sore throat, and dry cough. Although CoV also cause enteric and systemic diseases, most
infections are mild, resolving spontaneously.1
Despite the fact that the neurotropic, neuro-invasive and neurovirulent capabilities of SARS-CoV and MERS-CoV have been described in animals and humans leading to enceph-alitis, meningitis or encephalomyelitis, the specific
mecha-nisms of this process are not well characterized.2
SARS-CoV-2 was first described in Wuhan, China, in December 2019. In a few months, it has spread to nearly every country throughout the world, with large economic, social and health impacts, in addition to an overwhelming
num-ber of deaths.3 The clinical syndrome caused by SARS-CoV-2
is called 19. In a fair proportion of cases, COVID-19 symptoms are clinically indistinguishable from those of common flu, namely fever (90%), cough (70%), myalgia and fatigue (50%), less frequently headache (8%), and diarrhea (5%), while anosmia and ageusia may be initial
manifesta-tions.3 A smaller proportion of severe cases present more
intense lower respiratory tract disease, often requiring respi-ratory assistance. On the opposite side of the spectrum, 5% of
cases are asymptomatic.4 Moreover, as the pandemic unfolds,
there is growing evidence that COVID-19 is a multisystemic disease. For instance, renal failure is more common than ini-tially realized, whereas cardiac dysfunction has also been
well described in many SARS-CoV-2 infected individuals.5,6
Although the data are preliminary, a substantial propor-tion of patients develop neurological complicapropor-tions asso-ciated to COVID-19. Data from a series of patients from Wuhan, China, indicate that neurological abnormalities are
found in 36.4% of hospitalized patients.7 It is likely that this
figure may vary depending on several factors, such as clini-cal setting (outpatients versus inpatients), demographic fea-tures (age, sex, ethnicity) and methodology of neurological assessment.
The mechanism of neurological involvement in COVID-19 remains to be determined, but it is probably heterogeneous and multifactorial, including direct involvement of the brain due to SARS-CoV-2, auto-immune factors, inflammation (“cytokine storm”), drug side-effects, metabolic disturbances
and critical care neuropathy.8,9 The data from Wuhan show
that most complications have an early onset suggesting that direct involvement of the nervous system by the virus is an important factor. This is unlikely what happened with SARS, whose neurological findings had a late onset, suggesting an
underlying autoimmune mechanism.8
Absence of reports of phenomena such as chorea, myoc-lonus, opsoclonus and ataxia, and the scarcity of cases of acute demyelinating polyradiculopathy suggest that immune
mediated phenomena are not as common in COVID-19 although caution is warranted in interpreting such data, because many of these autoimmune manifestations have a prolonged latency. Moreover, there are descriptions of ataxia, stroke associated with antiphospholipid antibod-ies and even Guillain-Barré syndrome (GBS) in individuals
with COVID-19.7,10,11 Another important question about the
interplay between infection with SARS-CoV-2 and the ner-vous system is if pre-existing neurological diseases increase the risk of severe complications, such as respiratory failure in COVID-19. As of the writing of this review, there is no
evi-dence that this is the case.9 Yet, intuitively, one may argue
that conditions associated to respiratory issues (e.g., severe myopathies, neuropathies, neuromuscular junction disor-ders), as well as degenerative diseases, such as advanced Parkinson’s disease (PD), render subjects prone to a more malignant course of COVID-19. Despite the lack of data, one also expects worsening of neurological conditions as a result of COVID-19. Unpublished experience of the authors confirms this may happen in PD, which is not surprising, considering that it is well known that patients with under-lying degenerative disease, including dementing conditions, develop significant, often irreversible, worsening as a result of clinical disturbances. Other potential issues that may neg-atively interfere with the course of neurological illnesses are social isolation and lack of exercise due to staying at home
and social distancing.12
Finally, at a global level, the worsening of the pandemic has rightly led the health systems to focus on preventing and combating COVID-19. There is growing evidence that patients with other medical conditions are facing difficul-ties in accessing health providers despite a substantial increase in telemedicine. In the New York City area, for instance, there has been an 800% increase in cardiac arrest
deaths at home after the onset of the COVID-19 pandemic.13
As such, it is possible that people with neurological diseases are also having trouble in contacting their neurologists and the neurological community must strive to keep offering care to their patients despite the hardships created by the COVID-19 pandemic.
The aim of this article is to provide a review of the existing data, including epidemiology, pathophysiology, and clinical and laboratory findings of neurological findings in COVID-19.
METHODS
A literature search was performed following the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses guidelines14 in both MEDLINE and LILACS
databases, using “coronavirus COVID-19”, “COVID-19”, “COVID 19”, “SARS-CoV-2” as search terms, along with “neu-rology”, “neurological“ and the specific disorder designa-tions: cerebrovascular, stroke, encephalopathy, encephalitis,
meningitis, myelitis, Guillain Barré, Guillain-Barré syn-drome, myalgia, headache, hyposmia, anosmia, ageusia, in the medical subject headings, title, abstract, or author-sup-plied keywords. Research was broadened to include screen-ing of reference lists of systematic review articles for addi-tional studies initially missed or presented only in abstract form. No restrictions were predetermined as to the year of the study, with investigations dating from the earliest
avail-able date until May 10th, 2020. Only studies in English were
included. We analyzed publications with laboratory con-firmed cases only, ranging from relatively large series to more limited case series and case reports (Figure 1).
Figure 1 shows the flow diagram for inclusion of articles.
RESULTS
Table 1 presents a summary of the main findings of the review, which are described in more details below.
Cerebrovascular disease
Patients with SARS-CoV-2 infection, especially critically ill elderly cases, appear to be more susceptible to develop cere-brovascular disease (CVD), including cerebral hemorrhage and ischaemic stroke. The cases described so far indicate that ischaemic CVD in this setting may have distinct char-acteristics, with implications for diagnosis and treatment: the vast majority had large-vessel occlusion, and a significant
Figure 1. Inclusion of articles by Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 flow diagram.
Records iden�fied with database searching (n=146)
Scr
een
in
g
In
clude
d
Eli gi bili tyIden
�fi
ca
�on
Addi�onal records iden�fied withother sources (n=3)
Records a�er removing duplicates (n=62)
Records screened
(n=62) Records excluded (n=19)
Full-text ar�cles assessed for eligibility
(n=43 )
Full-text ar�cles excluded, not strictly related to the
topic (n=6) Studies included in qualita�ve synthesis (n=37) Studies included in quan�ta�ve synthesis (meta-analysis) (n=37)
number had multiple territories affected. Although some of the reported events were the first-ever in these patients med-ical history, most cases already had other cerebrovascular risk factors, such as hypertension, diabetes mellitus,
hyper-lipidemia, smoking or previous stroke history.15,16 On the
other hand, two recent reports identified a total of six cases of large-vessel stroke in SARS-CoV-2 patients younger than 50 (33–49) years of age. Three had no vascular risk factors, five had anterior circulation strokes, and all had mild to mod-erate symptoms of the viral infection. Most remained severely
disabled at last follow-up assessment.17,18
There is strong evidence that vascular complications may arise for the most part due to the well recognized potentially fatal inflammatory storm, which reflects a hyperactivation of inflammatory factors and dysfunction of the coagulation sys-tem, especially D-dimer and platelet abnormalities, increas-ing the risk of CVD. Furthermore, hypertense SARS-CoV-2 infected patients frequently develop changes in blood pres-sure, potentially explained by the fact that the virus spe-cifically binds to angiotensin converting enzyme 2 (ACE2) receptors. In addition, thrombocytopaenia, a risk factor for cerebral haemorrhage, is distinctively found in severe cases
of the disease.15 This equation may be further complicated by
cardiogenic and hematologic factors, as data from previous coronavirus and influenza epidemics suggest that viral infec-tions can trigger acute arrhythmias, exacerbation of heart
failure, and myocarditis.3,19 In turn, Zhang et al.10 described
severe coagulopathy, multiple infarcts (brain, upper and lower extremities), severe coagulopathy and the presence
of antibodies against cardiolipin and β2-glycoprotein I in
patients with SARS-CoV-2 infection.
The aforementioned evidence is partially corroborated by clinical data derived from a case series of SARS-CoV-2 infected
patients. Mao et al.7 identified neurologic symptoms in 45.5 %
of patients in a series of 88 severely infected patients, 5.7% of them presenting either ischemic or hemorrhagic CVD.
Asadi-Pooya and Simani20 published a systematic review of studies
on the neurological findings of SARS-CoV-2 infected patients, identifying ischemic CVD in about 5%, in addition to cases of cerebral venous sinus thrombosis and cerebral hemorrhage. CVD cases were significantly older, more likely to present with severe infection, to have cardiovascular risk factors, and to show increased serum markers of inflammatory response and hypercoagulable state. Overall, more than a third of these CVD patients eventually died. Although a pooled analy-sis of studies on this topic showed that stroke was associated to a 2.5-fold increase in odds of severe COVID-19, there was no statistically significant association of stroke with
mortal-ity.21 Figure 2 illustrates a case of SARS-CoV-2 infection
asso-ciated to cerebral hemorrhage seen by one of the authors of this review.
Finally, Khosravani et al.22 developed guidelines entitled
“Protected Code Stroke” for the management of hyperacute stroke during the coronavirus disease pandemic, providing considerations for screening, personal protective equipment and crisis resource management.
Encephalopathy
The largest data available on neurologic complica-tions associated to SARS-CoV-2 arose from a retrospec-tive case series of 214 hospitalized patients with confirmed
COVID-19.7 Out of the 214 patients (36.4%), 78 were found
Neurological
manifestation Frequency Presentation Risk factors / Associated features References
Cerebrovascular
disease 2.8–5.7% Mostly ischemic; rare hemorrhage and venous thrombosis Critically ill (?), pre-existing vascular risk factors 7,10,15,16,17,18,19,20,21 Encephalopathy (hypoxic)9%
Hypoxic encephalopathy; case reports of necrotizing hemorrhagic encephalopathy and
encephalitis
Critically ill, predictor of death 7,23,24,2,26,27,28,29,30,31
Guillain-Barré
Syndrome Rare
Six out of 11 cases reported presented variant forms, including
AMAN and MFS Only described in adults so far 11,38,39,40,41,42
Anosmia/ageusia 5.1–88% association; early feature with Both symptoms may occur in delayed resolution
Younger age, female; no correlation
with disease severity 7,45,46,47,48
Myalgia 10.7–54% Associated with fatigue, abnormal CK, and inflammatory markers Critically ill adults with multiple organ damage 7, 58,59,60,61,62 Headache 8–34% Non-specific Mostly benign; also described as part of severe processes 3,7,8,33 Other
manifestations N/A Ataxia, seizures, dizziness processes (encephalopathy, stroke)Described as part of severe 7,24,25,26 Table 1. Most common neurological manifestations of SARS-CoV-2 infection.
to have nervous system-associated manifestations, which were divided into three subgroups: central nervous sys-tem (CNS), peripheral nervous syssys-tem (PNS), and skeletal-related injury. CNS involvement, in particular, was seen in 53 patients (24.8%); these manifestations comprised dizzi-ness (n=36; 16.8%), headache (n=28; 13.1%), impaired con-sciousness (n=16; 7.5%), acute CVD (n=6; 2.8%), ataxia (n=1; 0.5%), and seizure (n=1; 0.5%). Among these CNS-related manifestations, impaired consciousness and CVD were sig-nificantly more common in patients with severe versus non-severe COVID-19 infection. The authors defined impaired consciousness as any change in level (e.g., somnolence, stu-por, and coma) and/or content of consciousness (e.g., con-fusional state and delirium). In other words, an encephalo-pathic state. As to seizures, there was one patient in the study who experienced acute limb twitching, foaming in the mouth and loss of consciousness for three minutes. Magnetic reso-nance imaging (MRI) and invasive procedures, such as lum-bar puncture, were avoided given the risk of cross-contam-ination. Therefore, it is not possible to further characterize
these patients’ encephalopathy with confidence.7
A similar retrospective study, also from China, included 274 patients with COVID-19: 113 deceased and 161 recovered
patients.23 Headache or dizziness were the initial presenting
symptoms in 31 patients (11%) and 21 patients (8%), respec-tively. Hypoxic encephalopathy was identified in 24 patients (9%). Whereas headache and dizziness were similarly seen
in the deceased and alive patient groups, hypoxic encepha-lopathy was more frequent in deceased patients (n=23/113) in comparison to those from the recovered patient group (n=1/161). The reported rate of confusional state was also 9% in a similar Chinese retrospective series involving 99 patients
with confirmed COVID-19 and pneumonia.24 In another
Chinese retrospective multicenter study with 304 patients who had been either discharged or died, eight were enceph-alopathic (2.6%; n=8/304): one obtunded, one delirious, and the remaining six comatose. Non-convulsive status
epilepti-cus was excluded as a cause for altered mental status.25
A French case series reported on neurologic compli-cations in a cohort of 58 patients with acute respiratory distress syndrome due to confirmed SARS-CoV-2
infec-tion.26 Confusional state and agitation were seen in roughly
two-thirds of patients. A total of 13 patients underwent brain MRI because of unexplained encephalopathy, eight of them showing leptomeningeal enhancement. Eight patients under-went electroencephalography (EEG), which only revealed non-specific changes. Lastly, cerebrospinal fluid (CSF) analyses of seven patients were negative for SARS-CoV-2. The authors speculated on the underlying mechanism of neurologic injury in these patients, raising the possibility of multifactorial factors, including intensive care unit (ICU) related encephalopathy, cytokine storm, and the effect or withdrawal of medications.
The first case of presumed COVID-19-associated acute
nec-rotizing hemorrhagic encephalopathy27 was of a middle-aged
Figure 2. Brain MRI of a 53 year-old, critically ill male admitted to intensive care unit due to severe SARS-CoV-2 pneumonia. Axial T-2 imaging shows bifrontal lesions which, added by additional sequences, suggested subacute parenchymal hematomas. Further imaging showed diffuse petechial hemorrhage throughout most of the hemispheric grey matter, suggestive of coagulopathy.
woman who presented respiratory symptoms along with fever and altered mentation. COVID-19 was confirmed with a nasopharyngeal swab. CSF studies were limited due to a traumatic lumbar puncture. The available tests reported by the authors included HSV-1, HSV-2, VZV and West Nile virus, which were all negative. SARS-CoV-2 was not tested in the CSF. Neuroimaging was remarkable for hemorrhagic, rim-enhancing lesions in the bilateral thalamus, medial tempo-ral lobes and subinsular regions. Computed tomography (CT) angiography and venography were normal. This patient was treated with intravenous immunoglobulin (IVIG), but details of outcome are unavailable. It is important to note the pre-sumptive nature of this diagnosis because SARS-CoV-2 was not tested in this patient’s CSF. Moreover, despite being rare, acute necrotizing encephalopathy may be caused by a myr-iad of pathogens, including influenza A and B, parainfluenza,
varicella, and HHV6.28 In addition, two other reports should
me mentioned. The first is a 54 year-old woman found uncon-scious at home and diagnosed with interstitial pneumonia due to SARS-CoV-2. Upon steady clinical deterioration, EEG showed focal frontotemporal seizure activity while brain and spine MRI revealed alterations of the periventricular white matter, bulbo-medullary junction and in both the cervi-cal and thoracic spinal cord, hyperintense in T2WI, without restriction of diffusion or contrast enhancement. CSF exami-nation was normal, including mutiple sclerosis markers and RT-PCR for SARS-CoV-2 and other viruses. The authors label the clinical presentation as brain and spine demyelinating lesions induced by a delayed immune response secondary
viremia.29 The second is a case of possible acute disseminated
encephalomyelitis (ADEM) described in a female patient in her early forties with acute dysphagia, headache, dysarthria and encephalopathy, nine days after presenting with fever
and respiratory symptoms.30 Chest imaging showed signs of
pneumonia, whereas brain MRI T2 FLAIR imaging showed extensive patchy areas of abnormal signal involving bilateral frontoparietal white matter, anterior temporal lobes, basal ganglia, external capsules and thalami suggestive of a demy-elinating process. Vascular imaging was normal. CSF analysis was also normal, including PCR for meningitis and encepha-litis causing agents. The testing for SARS-CoV-2 infection was positive. The patient was treated with hydroxychloroquine, ceftriaxone and a five-day course of IVIG with overall good response. A major caveat in this case is the fact that it was published in a non peer-reviewed source; thus, the
occur-rence of ADEM in this context still lacks confirmation.30
It was not until a few days later that the first confirmed
case of CNS infection by SARS-CoV-2 was published,31
con-firming the neuroinvasive properties of the virus. The patient was a 24 year-old man who developed headache, fatigue and fever roughly a week before presenting to the hospital due to a convulsive episode. Meningeal irritation was identified with examination warranting workup with a head CT and lumbar puncture. The former did not show cerebral edema, whereas
the latter revealed increased opening pressure (320 mm H2O),
mononuclear-predominant pleocytosis (12/uL), no red blood cells, and presence of SARS-CoV-2 RNA. Serum HSV-1 and VZV IgM antibodies were negative. Neuroimaging showed right mesial temporal encephalitis and right ventriculitis without abnormal enhancement; it also showed pan-parana-sal sinusitis. Chest imaging confirmed pneumonia, although nasopharyngeal swab was negative for SARS-CoV-2. This patient was treated with acyclovir, ceftriaxone,
vanco-mycin and steroids, as well as anti-convulsants.31
Later, three additional patients with SARS-CoV-2 infec-tion were reported as having meningoencephalitis presum-ably related to the virus. The first, a Chinese man, had the diagnosis of CNS infection based on clinical grounds — altered mentation and meningeal signs. This patient’s CSF studies were within normal limits, including negative testing for SARS-CoV-2, and head CT with no acute findings. Mental
confusion resolved by the time of discharge.32 The
sec-ond patient was a middle-aged woman who presented to an emergency department in the United States with fever, headache, and new-onset seizure. Initial examination was notable for meningeal signs. Head CT was normal, but CSF studies showed lymphocytic pleocytosis and increased pro-tein and red blood cells; SARS-CoV-2 was not tested and HSV PCR was negative. Although the patient did not have significant respiratory symptomatology, she tested positive for SARS-CoV-2. Her hospital course was complicated by encephalopathy despite no recurrence of seizures after anti-convulsant medication was initiated; EEG showed general-ized slowing only. There is no available information on
fol-low-up.33 The third case is of a 40 year-old man presenting
acute brainstem dysfunction three days after onset of symp-toms that eventually led to the diagnosis of SARS-CoV-2 infection. Brain and spine MRI showed changes in keeping with inflammation of the brainstem and the upper cervical
cord, leading to a diagnosis of rhombencephalitis.34 Altered
mental status, hyperreflexia and meningeal signs were also observed in a 64 year-old man from China, whose main symptoms were fever and respiratory-related symptoms; his testing was remarkable for negative SARS-CoV-2 in the CSF,
but positive in a throat swab.35
CNS involvement in the context of COVID-19 may be truly neurologic, a consequence of systemic injury, or a com-bination of both. The neurotropic nature of SARS-CoV-2 is
supported by the observation of viral spread into CSF35 and
the possible neuroinvasive potential of this virus. The latter is based on the similarity between SARS-CoV-2 and SARS-CoV, which in turn has established neuronal invasion
capabili-ties.36,37 Other possible mechanisms of CNS insult
second-ary to COVID-19 include hypoxic injury from lung disease, overactive systemic immune response and resultant cyto-kine storm (including IL-6, IL-12, IL-15, and TNF-alpha), and damage to endothelium and blood-brain-barrier resulting in
Guillain-Barré syndrome
GBS can potentially be linked to any viral infection and is a documented complication found in previous viral pan-demics, including those due to Zika, chikungunya, dengue,
and H1N1 influenza viruses.39 Due to the rising pandemics
of SARS-CoV-2 infection since the early months of 2020, vigi-lance for signs and symptoms of GBS should be part of the assessment of patients with SARS-CoV-2 infection given that, although a rare event in general, GBS is a potentially treat-able complication that may rise the viral infection lethality if not promptly identified.
As of the time of the writing of this review, 11 cases of
GBS potentially linked to SARS-CoV-2 have been reported.11
The first affected patient, published in early-April 2020, was a 61 year-old woman who returned to Shanghai from Wuhan in mid-January 2020, four days before presenting to medi-cal attention. At admission, she denied the typimedi-cal signs of SARS-CoV-2 infection, had normal lung auscultation and, as such, was not tested for it. Her complaints were of a one-day history of progressive fatigue and areflexic symmetric weak-ness in the lower extremities. Initial blood workup showed low lymphocyte count and thrombocytopenia. Three days after admission, symptoms were more profound, also affect-ing her upper extremities and added by a decreased sensa-tion to light touch and pinprick. At this point, CSF indicated normal cell count, but increased protein levels of 124 mg/ dL (8–43 mg/ dL). Nerve conduction studies performed on the fifth day after admission were in keeping with a diffuse demy-elinating process. A diagnosis of GBS was established and a course of IVIG was started. Eight days after admission (11 days since returning from Wuhan), she developed dry cough and fever (38.2°C), and a chest CT showed ground-glass opacities in both lungs. At this point, oropharyngeal swabs tested posi-tive for SARS-CoV-2 on RT-PCR assay. The patient was iso-lated, received supportive care and empirical antivirals (arbi-dol, lopinavir, and ritonavir). She improved gradually and was discharged 30 days after admission with normal global strength and reflexes, no respiratory symptoms, and a
nega-tive SARS-CoV-2 test.11 Although the patient was not tested
for the viral infection upon admission, the co-ocurrence of SARS-CoV-2 infection and GBS intuitively raises the possibil-ity of a causal relation. The pattern, however, is, if anything, that of a parainfectious process (based on the recent travel history and bloodwork findings on admission), rather than the classic post-infectious pattern reported during previous pandemics, Zika virus being the best example. Besides that, one can speculate that IVIG treatment may have triggered the presentation of symptoms and signs of the viral infection. The second case, published in mid-April, was of a 65 year-old male patient from Iran, presenting typical symp-toms of acute progressive symmetric ascending quadripare-sis, two weeks after been diagnosed with SARS-CoV-2 pneu-monia based on positive RT-PCR and chest CT imaging, and treated with hydroxychloroquine, lopinavir/ritonavir and
azithromycin. Neurophysiological study was consistent with acute axonal polyradiculopathy variant of GBS. CSF analysis was not performed due to a lack of consent, and the patient was treated with IVIG (0.4 g/kg/day for five days). No details
regarding the outcome were provided.40 At the same time,
another case of a 54-year-old male with a two-day history of numbness and progressive weakness of his lower extremi-ties was reported. Upon initial assessment, the patient also had fever and cough over the past 10 days, and diarrhea. Neurological examination confirmed an areflexic motor strength deficit. SARS-CoV-2 infection was confirmed with RT-PCR with chest imaging showing bilateral basilar lung opacities. Based on clinical presentation, the diagnosis of GBS was presumed even though the authors did not pursue further paraclinical confirmation and started IVIG (0.4 g/kg/day for five days) and hydroxychloroquine. The outcome was positive,
with improvement in respiratory and neurological status.41
The most solid report on this topic came from Italy, including five patients diagnosed with GBS after RT-PCR con-firmed SARS-CoV-2 infection. Presentation were lower-limb weakness and paresthesia in four patients and facial diple-gia followed by ataxia and paresthesia in one patient, with tetraplegia evolving over a period of 36 hours to four days in four patients. The interval between the onset of SARS-CoV-2 infection and GBS symptoms ranged from five to 10 days. CSF analysis showed normal white cell count in all of them, and elevated protein in three. Electrophysiological studies were consistent with an axonal variant of GBS in three patients, and a demyelinating process in two. All patients were treated with IVIG, one had a repeated IVIG course and another one was treated with plasma exchange. Outcomes varied: four weeks after treatment, two remained in the ICU receiving mechanical ventilation, two were still recovering with signifi-cant weakness, and one had been discharged, able to walk
independently.42
Another Italian report arguably had a parainfectious pre-sentation and was, unfortunately, the first fatal case of GBS in this setting: a 71 year-old man with rapidly progressive ascending tetraparesis, paresthesias, and areflexia. CSF and nerve conduction studies confirmed a severe form of acute polyradiculoneuritis with prominent demyelinating features. Given that the patient also presented with a one-week com-plaint of fever and dyspnea, he was tested for SARS-CoV-2 infection and underwent a chest CT, testing positive for COVID-19 pneumonia. Despite prompt treatment with IVIG, antiviral therapy (lopinavir and ritonavir), and hydroxychlo-roquine in intensive care setting, the patient died a few hours
after admission.43
Finally, a Spanish report of two cases, one present-ing with anosmia, ageusia, oculomotor palsy, ataxia, are-flexia, albuminocytologic dissociation and positive testing for GD1b-IgG antibodies, five days after developing cough, malaise, headache, low back pain and fever with positive RT-PCR for SARS-CoV-2; and another of a 39 year-old man
with ageusia, bilateral abducens palsy, areflexia and albu-minocytologic dissociation, three days after developing diarrhea and fever with positive testing for SARS-CoV-2 virus infection. The first patient was treated with IVIG and both made a complete neurological recovery, except for
residual anosmia and ageusia.44
Until the writing of the present review, there seems to be reasonably good evidence for an association of SARS-CoV-2 infection, GBS and GBS variants. Furthermore, the apparent dysproportional frequency of axonal damage raises the pos-sibility of the occurrence of more severe forms in this setting. Awareness for this specific complication is advised, as well its inclusion in the differential diagnosis of cases with suspected critical-illness polyneuropathy. Conversely, it also seems rea-sonable to test new GBS cases for the virus during the ongo-ing pandemic.
Olfactory and taste disorders
Anosmia or hyposmia refer, respectively, to the absence or reduction of the sense of smell, whereas ageusia is the loss of taste. Both conditions, anosmia or ageusia, may occur in isolation (idiopathic) or associated with struc-tural damage to the nervous system. Several neurological diseases may present with olfactory impairment, such as head trauma, multiple sclerosis, PD and Alzheimer’s
dis-ease.45 More frequently, 11 to 40% of patients with upper
air-way tract infection, common cold or influenza may present
anosmia or hyposmia.46
Recently, a few studies have identified both anos-mia and ageusia as frequent and marked clinical features
observed in SARS-CoV-2 infection. Giacomelli et al.47
evalu-ated, with a simple questionnaire, 88 hospitalized patients with SARS-CoV-2 infection, detecting olfactory or taste dis-orders in 33.9% of patients, whereas both were subjectively detected at the same time in almost 20% of them. In terms of timing for the detection of these symptoms, 20.3% presented anosmia before admission, and for ageusia, 91% described it before hospitalization. This study also observed that olfac-tory and/ or taste disorders were more frequent in female and young patients.
In a larger multicentric study evolving 12 centers, Lechien
et al.48 evaluated 417 patients with SARS-CoV-2 infection, and
observed that 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively, and recovery rate was 44% in a short period. It is noteworthy that 11.8% of the patients had olfactory dysfunction as the presenting symp-tom. This study also showed that females were significantly more affected.
Beltrán-Corbellini et al.49 evaluated the frequency of taste
and smell disorders in patients with SARS-CoV-2 infection and compared them to patients with influenza infection as a control group, showing that these deficits were significantly more frequent in SARS-CoV-2 infection than in the controls. Moreover, another study demonstrated that patients with
SARS-CoV-2 infection may present isolated anosmia,
with-out other upper airway infection symptoms or signs.50
Although pathophysiological mechanisms related to anosmia and ageusia in SARS-CoV-2 are not completely understood, a mouse model has demonstrated
penetra-tion of the virus through the olfactory bulb.51 Furthermore,
the cells of the oral mucosa are comprised by ACE2
recep-tor, which is used by the virus to infiltrate into the cells.52
A dopaminergic pathway dysfunction is also presumed to
be related to anosmia in patients infected by SARS-CoV-2.53
Finally, SARS-CoV-2 may infect the inner lining of the nasal
cavity, triggering localized inflammation.51
Overall, anosmia and ageusia are very common in SARS-CoV-2, more frequently than observed in other upper airway infections, and must be included as a clinical clue to guide the investigation through serology or PCR testing. There is no specific treatment for anosmia and ageusia related to SARS-CoV-2 infection, recovery is variable and should occur in most of the affected patients after two or three weeks. A follow-up reassessment will be necessary to determine if these symptoms are indeed transient findings or permanent sequelae of SARS-CoV-2 infection.
Myalgia
Myalgia is a common symptom in the neurological clini-cal practice, which, in isolation, often represents a
non-spe-cific manifestation of several conditions.54 In addition,
myal-gia has to be differentiated from mimics, such as cramps, which are often associated to diseases of the peripheral ner-vous system and muscles, whereas myalgia is more often a
clue to a muscle disease per se.55 This symptom has a
rela-tively broad differential diagnosis, ranging from metabolic
myopathies to a side effect of the use of statins.56
Brazil, among a few other countries, has recently wit-nessed epidemics of arbovirus infections, including Zika, chikungunya and dengue viral diseases, which present with ample spectra of neurological complications, including meningoencephalitis, myelitis, radiculitis, GBS, and myosi-tis. Myalgia, in or out of the context of myositis, is one of the most common symptoms of this group of arbovirus, besides
infections by influenza viruses.57,58,59
During the ongoing pandemics of SARS-CoV-2 infec-tion, descriptions of muscle involvement have been
consis-tently reported.7,8,60,61,62,63,64 The aforementioned study by Mao
et al.,7 a retrospective observational study of 214
hospital-ized patients in the city of Wuhan, China, recognhospital-ized mus-cle involvement in 19.3% of patients. When compared to the patients without muscle symptoms, patients with myalgia had higher serum titers of creatine kinase (CK), regardless of symptoms severity. Myalgias correlated with higher neu-trophil and lower lymphocyte counts, higher C-reactive pro-tein and D-dimer levels, indicating increased inflammatory response and blood coagulation function. In addition, these patients had multiorgan damage, including more severe liver
and kidney laboratory abnormalities. Unfortunately, this publication did not explore other paraclinical markers used to assess the peripheral nervous system, such as nerve con-duction studies/electromyography, CSF analysis, and muscle
biopsy.7 Another study from Wuhan with five patients with
pneumonia due to coinfection with SARS-CoV-2 and
influ-enza viruses, demonstrated that 40% of them had myalgia.60
Li et al.61 performed a systematic literature review
search of the main online databases from December 2019 to February 2020, totaling 1,994 patients with COVID-19 and concluding that 35.8% of these cases presented myalgia or fatigue. The study did not perform a correlation analysis of
these symptoms with any other variable. Huang et al.62
col-lected data prospectively on 41 hospitalized cases of COVID-19, all presenting with pneumonia and abnormal chest CT imaging, and observed myalgia or muscle fatigue in 44% of them, but reaching 54% among cases admitted to the ICU. Accordingly, CK and lactate dehydrogenase serum levels were elevated in 33 and 73%, respectively, for all patients, reaching 46 and 92%, respectively, for ICU patients.
Rhabdomyolysis associated with myalgia and fatigue has also been described in cases with severe COVID-19
with potential implications on renal function.63 Finally, Han
et al.64 compared the findings of 25 adults and seven children
with confirmed COVID-19, observing that myalgia was dis-proportionally more common among adults, reaching 52%, although the children had elevated CK levels more frequently than adults (57.1 vs. 4%).
Other neurological manifestations
In addition to the conditions mentioned above, other neurological symptoms, signs and potential complications have been described in SARS-CoV-2 infection. Headache, a non-specific and frequent symptom in common upper air-way infections and, in fact, in infections in general, has been described almost invariably in a series of patients
with SARS-CoV-2.65 In this scenario, however, considering
that meningeal involvement and CVD are part of the clini-cal spectrum of the presentation of SARS-CoV-2 infection, it is essential to rule out meningo-encephalitis and cerebral venous thrombosis in infected patients with refractory or
persistent headache. Finally, although unusual, Mao et al.7
have reported epilepsy, dizziness, and ataxia in patients with SARS-CoV-2 infection.
CONCLUSIONS
In conclusion, we aimed at pointing out the main neuro-logical manifestations described in SARS-CoV-2 infection, as of the writing of this review. Their frequency is relevant, occur-ing in more than one third of the hospitalized patients and varying from mild (i.e., hyposmia and myalgia) to life-threat-ening complications, such as encephalopathy and stroke. The existing data on the pathophysiological mechanisms contributing to some of these neurological manifestations in the context of SARS-CoV-2 infection reinforce the idea that this virus may be neuroinvasive and/or affects directly or
indirectly the CNS or the PNS.66 As the pandemic unfolds,
pathological studies will be needed to isolate SARS-CoV-2 from neuronal cells, CSF and endothelium of cerebral vessels. Recognition of neurological manifestations of SARS-CoV-2 should be emphasized despite the obvious challenges faced by clinicians caring for critical patients who are often sedated and presenting other concurrent systemic complications.
Finally, the intuitive concern regarding the potential inter-ference of disease modifying agents used for the treatment of immunomediated neurological disorders, such as multiple sclerosis and neuromuscular disorders, has been addressed in a few recent publications that should be of interest to clini-cians involved in the care for these patients within the
ongo-ing COVID-19 pandemic.67,68
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